May 20, 2013

This is a nice little review of the state of the art in germline mutation rate estimation in humans. This was previously estimated using paleontological calibrations (especially the human/chimp split), but a slower mutation rate emerged on the basis of whole genome data from humans. There may be problems with the latter (because of false positive/negative mutations using whole genome sequencing), but the problem is an important one due to the use of the mutation rate to estimate time depth of common ancestry. In any case, the table on the left summarizes the results of several studies on the topic.

Trends in Genetics, 17 May 2013
doi:10.1016/j.tig.2013.04.005

Properties and rates of germline mutations in humans

Catarina D. Campbell, Evan E. EichlerSee Affiliations

Summary

All genetic variation arises via new mutations; therefore, determining the rate and biases for different classes of mutation is essential for understanding the genetics of human disease and evolution. Decades of mutation rate analyses have focused on a relatively small number of loci because of technical limitations. However, advances in sequencing technology have allowed for empirical assessments of genome-wide rates of mutation. Recent studies have shown that 76% of new mutations originate in the paternal lineage and provide unequivocal evidence for an increase in mutation with paternal age. Although most analyses have focused on single nucleotide variants (SNVs), studies have begun to provide insight into the mutation rate for other classes of variation, including copy number variants (CNVs), microsatellites, and mobile element insertions (MEIs). Here, we review the genome-wide analyses for the mutation rate of several types of variants and suggest areas for future research.

1 comment:

There is still one major assumption about the genome mutation rate that has not yet been supported with data. We are still assuming that all populations have the same genome mutation rate.

In these direct analyses of whole genomes, 96 families have been analyzed. 85 are European, 1 is Sub-Saharan and 10 are not reported, but likely to be European. This represents a major gap in understanding. It will be very interesting to see the results from the final phase of the 1000 genomes project when they report on whole genome trio data for multiple families across diverse populations.

There are a number of lines of evidence to suggest that there may be differences between populations on mutation frequency.

1) The only data point from the YRI family that we have suggests that there is a 5-fold increase in mutation rate from the maternal YRI contribution relative to the CEU maternal contribution.

2) Evidence suggests that the SNP : microsatellite mutation ratio is increased in Sub-Saharan populations relative to Eurasians. (This may suggest that SNP mutability is increased in Sub-Saharan Africans whereas microsatellite mutability may be more constant across populations)

3) There is strong evidence that differences in PDRM9 between populations dramatically shifts recombination hotspots and linkage disequilibrium patterns across populations, why couldn't SNP mutations also differ across populations?

4) There is evidence that the rates of de novo mutations are not uniform across the genome. This suggests there is a biological root cause for the appearance of germline mutations, if there are differences between populations in the enzymes involved in the biology of de novo mutations, wouldn't this also result in differences in the frequency or landscape of these mutations?

There are many other reasons to suspect differences of mutation frequency between populations, but I think it is something that people don't like to discuss because it will mean going back to the drawing board on a number of critical assumptions that we have made about human history. Don't be surprised though when the final 1000 Genomes report comes out and it reveals a difference in mutation rate between populations.

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